Microbicides have been one of the most successful weapons against infectious diseases, and are of particular importance in situations where the state-of-the-art treatment of the given infectious disease is difficult or ineffective. Most viral pathogenic agents causing severe diseases belong to this category . In the applicant's pilot experiments, he has defined peptidic molecules with anti-HIV-1 activities in vitro. Here he proposes studies that will provide guidance in the further development of these and other antiviral peptides that may be used as agents inhibiting sexual transmission of HIV. Both in vitro and in viva methods assessing their antiviral capacity will be employed. The focus of the first Specific Aim is to test antiviral effects using several HIV /SIV /SHIV- permissive cell lines as well as primary human and simian PBMC. Assays assessing, infectivity , cell fusion and potential virucidal effects of the peptides will be utilized together with several different isolates of HIV-1, SIV, and SHIV. These experiments may improve our understanding of the mechanism of their antiviral action. In addition, potential toxicities of the compounds will be analyzed in vitro. The main objective of the second Specific Aim is to investigate the hypothesis that a simple formulation containing an antiviral peptide (or several of them) applied to a mucosal surface is able to block the infection caused by the exposure of the mucosal surface to immunodeficiency viruses. This will be tested in the applicant's system of mucosal SIV/SHIV infection of rhesus macaques (Macaca mulatta). Successful outcomes of these experiments may result in designing novel anti-HIV chemoprophylactic agents.